bims-mihora 2026-01-25 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2026–01–25
sixteen papers selected by
Lisa Patel, Istesso

CD36 regulates myogenic differentiation via chronic integrated stress response - implications for muscle aging.
Integrated Stress Response and Drug-Induced Acute Kidney Injury: Involvement of ATF4-STAT1-GBP2 Signaling.
The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise.
C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.
UBR4 Attenuates Cisplatin-Induced Acute Kidney Injury by Regulating the HRI-ISR Axis.
Internal-Friction Network Piezoelectric Hydrogel Microspheres Achieve Physiological Electrical Adaptation to Regulate Mitochondrial Autophagy in Degenerative Tissues.
The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.
Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.
Cockayne syndrome mutation in XPG activate the integrated stress response.
CircRNA HIPK2-mediated metabolic reprogramming restores mitochondrial homeostasis in chondrocytes through the miR-206/Sirt3 signaling axis attenuating osteoarthritis-induced nociception.
Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.
Bone-targeted mitochondrial delivery via magnetic-temperature responsive artificial cells for repairing age-related fractures.
Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice.
The dual role of activating transcription factor 4: from cellular stress sentinel to cardiovascular disease intervention.
Blood, sweat, tears and fibrosis: when overtraining injures the liver.
Integration of Bioinformatics and Experiments to Identify Mitochondrial Metabolism and Immune Infiltration Characterization in Lung Injury and Post-Injury Lung Fibrosis.

J Muscle Res Cell Motil. 2026 Jan 22. 47(1): 2

CD36 regulates myogenic differentiation via chronic integrated stress response - implications for muscle aging.

Xin Ye, He-Qiang Jia, Chen Yuan, Hui Sun, Ying Dong, Dan Wang, Zhen-Jiang Wang, Zhi Chen, Chun-Yan Yu.

  The integrated stress response (ISR) and mitochondrial unfolded protein response (UPRmt) plays a vital role in myogenic differentiation of muscle satellite cells. In this study, chronic ISR and UPRmt was induced with impaired myogenic differentiation and cluster of differentiation 36 (CD36) was highly expressed and localized on the mitochondria in aging muscle. Little is known about the interplay of CD36 and ISR during differentiation. Knocking down CD36 expression at day 3 in differentiated C2C12 myoblasts indicated that the expression levels of Activating transcription factor 4 (ATF4), and other ISR - related proteins decreased, but the expression levels of UPRmt - related proteins Activating transcription factor 5 (ATF5), Heat Shock Protein 60(HSP60) and Heat Shock Protein 10(HSP10) increased with mRNA level of HSP60 increased. Meanwhile Myogenin (MyoG) expression level was increased but Myosin heavy chain 1 (Myh1) expression level was decreased. Following CD36 knockdown, mito-nuclear protein imbalance and mitochondrial dysfunction occurred. Interaction between CD36 and Mammalian Target of Rapamycin (mTOR) was observed in aging muscle. Collectively, CD36 was localized on the mitochondria in aging muscle, while CD36 was associated with ISR and UPRmt early during myogenic differentiation in C2C12 myoblasts, which could have implications for the development of new strategies to treat sarcopenia.

Keywords:  CD36; ETC; ISR; Sarcopenia; UPRmt ; mTOR

DOI:  https://doi.org/10.1007/s10974-025-09719-6
J Am Soc Nephrol. 2026 Jan 20.

Integrated Stress Response and Drug-Induced Acute Kidney Injury: Involvement of ATF4-STAT1-GBP2 Signaling.

Hongli Zhang, Xiaoyan Sun, Yilan Shen, Yuting Li, Zhentian Nie, Zhengyang Chen, Yawei Kong, Zhe Chen, Xiaohan Liu, Dingkun Gui, Wei Chen.

BACKGROUND: Pyroptosis plays a critical role in eliminating pathogens and facilitating tissue repair; however, sustained pyroptosis-driven inflammation accelerates kidney injury and disease progression. Thus, elucidating the mechanisms governing pyroptosis is essential for developing effective therapies for inflammatory kidney diseases such as acute kidney injury (AKI), which currently lacks specific treatment options.
METHODS: Changes in tubular epithelial cells following drug-induced AKI were assessed using single-cell RNA sequencing, immunohistochemistry, and immunofluorescence. Mechanistic insights were obtained through RNA sequencing, genomic manipulation, transcriptomic profiling, luciferase reporter assays, co-immunoprecipitation, and Western blotting. Tubular epithelial cell fate was further evaluated using transgenic mouse models and pharmacological interventions.
RESULTS: We identified activating transcription factor 4 (ATF4) as a key regulator of inflammation in drug-induced AKI. As the master regulator of the integrated stress response, ATF4 was markedly upregulated in renal tubules and positively correlated with kidney dysfunction in both human and murine AKI models. The specific deletion of ATF4 in tubular epithelial cells significantly ameliorated kidney dysfunction, inflammation, and mitochondrial apoptosis, whereas ATF4 activation exacerbated these pathological features. Mechanistically, ATF4 suppression inhibited STAT1 phosphorylation and disrupted its interaction with GBP2, thereby attenuating NLRP3 inflammasome activation, preventing tubular epithelial cells' pyroptosis, and improving kidney function. Notably, inhibition of ATF4-either pharmacologically using our prioritized integrated stress response antagonist ERMT1 or through engineered nanobiologics-mediated silencing of tubular epithelial cells-significantly reduced renal inflammation and injury.
CONCLUSIONS: ATF4 promoted pyroptosis in drug-induced AKI through STAT1-GBP2 signaling.

DOI: https://doi.org/10.1681/ASN.0000000984
Compr Physiol. 2026 Feb;16(1): e70105

The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise.

Chenliang Zhang, Ting Zhang, Qiulin Tang, Yu Zeng, Dan Cao.

  The integrated stress response (ISR) is an evolutionarily conserved signaling pathway that converges diverse cellular stresses onto the eIF2α-ATF4 axis, thereby orchestrating a fundamental decision between adaptive survival and cell death. In cancer, malignant cells exploit the ISR to cope with microenvironmental pressure, yet strong or persistent ISR activation can also trigger apoptosis, highlighting its therapeutic potential. However, this duality complicates the targeting of the ISR for cancer therapy. In this review, we systematically outline the upstream regulators and downstream effector networks of the ISR, analyze its context-dependent functions, encompassing both tumor-promoting and tumor-suppressing activities, in tumorigenesis, immune modulation, and therapy resistance, and evaluate the rationale for targeting the ISR under defined conditions. We also comprehensively summarize and discuss recent advances in ISR-targeting agents, including both inhibitors and activators, under preclinical and clinical development, assessing their potential and current constraints. Although numerous challenges remain in therapeutically harnessing the ISR, we conclude that a deeper mechanistic understanding of how the ISR governs cell fate will further establish the ISR as a promising and actionable target for future cancer therapeutics.

Keywords:  ATF4; apoptosis; drug resistance; eIF2α; integrated stress response; tumor immunotherapy; tumor therapy

DOI:  https://doi.org/10.1002/cph4.70105
Autophagy. 2026 Jan 22.

C3orf33/MISO regulates mitochondrial homeostasis via mitophagy.

Jianshuang Li, Wenjun Wang, Li He, Qinghua Zhou.

  Mitochondria maintain homeostasis through dynamic remodeling and stress-responsive pathways, including the formation of specialized subdomains. Peripheral mitochondrial fission generates small MTFP1-enriched mitochondria (SMEM), which encapsulate damaged mtDNA and facilitate its macroautophagic/autophagic degradation. However, the underlying mechanism governing SMEM biogenesis remains unclear. In our recent study, we identified C3orf33/CG30159/MISO as a conserved regulator of mitochondrial dynamics and stress-induced subdomain formation in Drosophila and mammalian cells. C3orf33/MISO is an integral inner mitochondrial membrane (IMM) protein that assembles into discrete subdomains, which we confirm as small MTFP1-enriched mitochondria (SMEM). Mechanistically, C3orf33/MISO promotes mitochondrial fission by recruiting MTFP1 to activate the FIS1-DNM1L pathway while suppressing fusion via OPA1 exclusion. Under basal conditions, MISO is rapidly turned over and contributes to mitochondrial morphology maintenance. Upon specific IMM stresses (e.g. mtDNA damage, OXPHOS dysfunction, cristae disruption), C3orf33/MISO is stabilized, thereby initiating SMEM assembly. These SMEM compartments function as stress-responsive hubs that spatially coordinate IMM reorganization and target damaged mtDNA to the periphery for lysosome-mediated clearance via mitophagy. Together, we address these fundamental gaps by identifying C3orf33/MISO as the key protein that controls SMEM formation to preserve mitochondrial homeostasis under stress.

Keywords:  Homeostasis; MISO; SMEM; mitochondrial subdomains; mitophagy

DOI:  https://doi.org/10.1080/15548627.2026.2621110
Free Radic Biol Med. 2026 Jan 16. pii: S0891-5849(26)00033-X. [Epub ahead of print]

UBR4 Attenuates Cisplatin-Induced Acute Kidney Injury by Regulating the HRI-ISR Axis.

Zeyu Tang, Chen Li, Cheng Yang, Xinghua Chen, Maoqing Tian, Liwen Qiao, Jiefei Zeng, Wenjing Zhen, Wei Liang, Lunzhi Liu, Huiming Wang, Xiangyou Li, Lu Zhang.

  Cisplatin is widely used in treating solid tumors, but its dose-limiting nephrotoxicity, which manifests as acute kidney injury (AKI), remains a major clinical challenge. The molecular pathways determining proximal tubular epithelial cell (PTEC) susceptibility during cisplatin-induced injury are not fully elucidated. Here, we identify ubiquitin protein ligase E3 component n-recognin 4 (UBR4) as a key regulator of the integrated stress response (ISR), which plays an important role in regulating reactive oxygen species (ROS) accumulation and mitophagy in the kidney. UBR4 expression was markedly upregulated in PTECs of mice with cisplatin-induced AKI. Tubule-specific Ubr4 deficiency exacerbated kidney dysfunction, tubular damage, and cell death. Mechanistically, UBR4 promoted ubiquitination and degradation of the kinase HRI, thereby constraining ISR overactivation and alleviating its inhibitory effect on mitophagy. Consistent with this mechanism, both genetic enhancement of UBR4 and pharmacological inhibition of the ISR with ISRIB significantly mitigated cisplatin-induced nephrotoxicity. Together, our findings uncover a previously unrecognized UBR4-HRI-ISR regulatory axis that serves as an intrinsic protective mechanism in the kidney and highlight UBR4 as a promising therapeutic target for preventing cisplatin-induced tubular injury.

Keywords:  HRI; UBR4; acute kidney injury; integrated stress response; mitophagy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.025
Adv Mater. 2026 Jan 21. e19152

Internal-Friction Network Piezoelectric Hydrogel Microspheres Achieve Physiological Electrical Adaptation to Regulate Mitochondrial Autophagy in Degenerative Tissues.

Huzhe Liu, Fan Wang, Weiwei Yi, Siyuan Huang, Zixiang Tang, Bo Liao, Zhenming Hu, Wenguo Cui, Jieliang Shen.

  Mitochondrial autophagy imbalance critically drives apoptosis and tissue degeneration, requiring physiological electrical adaptation to meet cellular thresholds. However, degenerative tissues exhibit deficient endogenous electrical signals, disrupting cellular energy transfer. Using supramolecular engineering and microfluidic strategies, we constructed an internal-friction network hydrogel microsphere system through synergistic assembly of piezoelectric bismuth ferrite nanoparticles (BF) and sliding-ring-functionalized methacrylated hyaluronic acid (HAMA), achieving physiological electrical adaptation in degenerative tissues. BF convert mechanical stimuli into electrical signals, while the stress-dependent internal-friction network regulates energy dissipation. Under low stress, sliding-ring movement produces low friction with mechanoelectrical conversion loss of 61.5 kJ/m3, enhancing electrical generation. Under high stress, main chain straightening increases friction to 78.3 kJ/m3, suppressing excessive signals and restoring physiological electrical adaptation. The microspheres generate stable electric fields (95-110 mV/mm) under dynamic loading, promoting mitochondrial autophagy via PINK1/Parkin pathway activation, maintaining stable mitochondrial membrane potential (compared with OS group, the JC-1 ratio increases by 49.2%), and reducing nucleus pulposus apoptosis by 75%. In vivo experiments demonstrated that microsphere implantation restored the physiological electrical environment, enhanced mitochondrial autophagy, inhibited apoptosis, and delayed intervertebral disc degeneration progression, providing new insights for treating degenerative tissues through electrical adaptation restoration.

Keywords:  hydrogel microspheres; internal‐friction network; intervertebral disc degeneration; mitochondrial autophagy; piezoelectricity

DOI:  https://doi.org/10.1002/adma.202519152
Mol Neurobiol. 2026 Jan 19. 63(1): 372

The Interplay Between Nurr1 and Mitochondrial Biogenesis: Implications for Neurodegenerative Therapy.

Simranjeet Kaur, Ashi Mannan, Thakur Gurjeet Singh.

  The transcription factor Nurr1 (NR4A2) serves as an essential element in dopaminergic neuron development since it functions predominantly in the substantia nigra, which becomes severely affected during Parkinson's disease (PD) and Alzheimer's disease (AD). Nurr1 regulates dopamine synthesis, survival-promoting, and oxidative stress genes that affect mitochondrial formation. Nurr1 binds to PGC-1α, allowing for mitochondrial activity regulation. This relationship supports mitochondrial biogenesis. Post-translational changes, including phosphorylation and acetylation, modify Nurr1 transcriptional regulation in order to enhance its ability to regulate mitochondrial genes. The assessment examines Nurr1's involvement in dopaminergic neuron development and mitochondrial formation while showing its role in reducing oxidative damage for an extensive understanding of its neurological disease functionality. Nurr1 serves as a therapeutic candidate for analysis, while the review explores obstacles and potential paths for using Nurr1-based treatments against Parkinson's disease alongside Alzheimer's disease and other neurodegenerative disorders. The extensive research utilized multiple databases, PubMed, Scopus, Medline, and EMBASE, with keywords "Nurr1," "NR4A2," "Neurodegenerative disorders," "Mitochondrial biogenesis," "Oxidative stress," "Parkinson's disease," "Alzheimer's disease," and "Therapeutic target." The analysis examined published research regarding Nurr1-mediated control of dopaminergic function and survival and mitigation of neurological and mitochondrial deficits within the past decade. Nurr1's interactions with important co-regulators like PGCα, its post-translational changes, and its effects on neuroinflammation have also received particular focus. In neurodegenerative illnesses, mitochondrial dysfunction adds to neuronal damage. Nurr1's regulation of mitochondrial biogenesis helps recover mitochondrial function, alleviate oxidative stress, and sustain neuronal survival. Dysregulation of Nurr1 expression is connected to decreased mitochondrial activity and accelerated neurodegeneration.

Keywords:  Alzheimer’s disease; Mitochondrial biogenesis; Neurodegeneration; Nurr1; Oxidative stress; PGC-1α; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12035-025-05633-7
Sci Rep. 2026 Jan 17.

Parkin overexpression attenuates muscle atrophy and improves mitochondrial bioenergetics but not histological features of Duchenne muscular dystrophy in mice.

Olivier Reynaud, Marie-Belle Ayoub, Jean-Philippe Leduc-Gaudet, Marina Cefis, Marc P Lussier, Sabah Na Hussain, Gilles Gouspillou.

Duchenne Muscular Dystrophy (DMD) is the most common childhood muscular disorder. Mitochondrial dysfunctions are key disease features of the disease, and strategies that improve mitochondrial health have emerged as promising to slow disease progression. Emerging evidence indicates that impaired/insufficient mitophagy may contribute to the accumulation of mitochondrial dysfunction seen in patients and animal models of DMD. We therefore hypothesized that overexpressing Parkin, a key mitophagy regulator, may improve mitochondrial and muscle health in a mouse model of DMD. To this end, Parkin was overexpressed using intramuscular injections of adeno-associated viruses performed in 5-week-old and 18-week-old D2.B10-Dmdmdx/J mice (D2.mdx), a widely used mouse model of DMD. Four and 16 weeks of Parkin overexpression initiated in 5-week-old and 18-week-old D2.mdx, respectively, resulted in muscle hypertrophy, as indicated by an increase in muscle mass and fiber cross-sectional area. While Parkin overexpression did not impact maximal mitochondrial respiration or mitochondrial content, it increased the Acceptor Control Ratio, an index of mitochondrial bioenergetic efficiency. Parkin overexpression also decreased mitochondrial H2O2 emission, a surrogate for mitochondrial ROS production. However, Parkin overexpression failed to reduce the proportion of fibers with central nuclei and markers of muscle damage and/or necrosis. Taken all together, our results indicate that Parkin overexpression can attenuate muscle atrophy, improve mitochondrial bioenergetics and lower mitochondrial ROS production in a mouse model of DMD. These findings showcase the partial beneficial effects of overexpressing Parkin in ameliorating some, but not all, pathological features observed in a mouse model of DMD.

DOI: https://doi.org/10.1038/s41598-025-34223-9
Hum Genet. 2026 Jan 21. 145(1): 15

Cockayne syndrome mutation in XPG activate the integrated stress response.

Danhui Zhang, Max Hartmann, Zhouli Cao, Gaojie Zhu, Gregoire Najjar, Cagatay Günes, Steffen Emmert, Karin Scharffetter-Kochanek, Sebastian Iben.

Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are diseases provoked by mutations in multifunctional proteins that are involved in DNA repair. DNA-repair deficiency explains the high cancer incidence of XP, whereas cancer-free CS, characterized by growth retardation, neurological degeneration, and premature aging does not present as a classical DNA-repair deficiency disorder. Here, we compared a severe combined XP/CS case provoked by XPG-mutation with an XP "only" patient cell line caused by mutation in the same XPG gene to carve out the pathogenic cellular disturbances that provoke CS. We identified RNA polymerase I transcription and rRNA maturation defects, a highly phosphorylated eukaryotic initiation factor 2 alpha (eIF2alpha), and a shift from cap- to internal ribosomal entry site (IRES) translation, indicating an activated integrated stress response in CS. Disturbances in ribosomal biogenesis and translational control might thus contribute to the development of CS.

DOI: https://doi.org/10.1007/s00439-025-02804-3
Inflammopharmacology. 2026 Jan 20.

CircRNA HIPK2-mediated metabolic reprogramming restores mitochondrial homeostasis in chondrocytes through the miR-206/Sirt3 signaling axis attenuating osteoarthritis-induced nociception.

Jian Shen, Tao Hong, Xue Li.

  Osteoarthritis (OA) is a degenerative joint disorder marked by chondrocyte metabolic dysfunction and mitochondrial impairment. This study elucidates the role of circHIPK2, a circular RNA downregulated in OA chondrocytes, in regulating glucose metabolism and mitochondrial homeostasis through the miR-206-SIRT3 axis. Clinical samples revealed significant circHIPK2 reduction and miR-206 upregulation in OA chondrocytes, correlating inversely with SIRT3 expression. In vitro LPS-induced injury models demonstrated that circHIPK2 overexpression mitigated chondrocyte apoptosis and metabolic stress, while miR-206 inhibition reversed LPS-driven glycolytic activation and mitochondrial dysfunction. Mechanistically, circHIPK2 directly bound miR-206 via Ago2-dependent interactions, as confirmed by RNA pull-down and luciferase assays, thereby alleviating miR-206-mediated suppression of SIRT3, a key mitochondrial deacetylase. Rescue experiments in chondrocytes showed that SIRT3 restoration rescued miR-206-induced metabolic defects, including impaired oxidative phosphorylation and ATP depletion. In vivo, intra-articular delivery of circHIPK2 in a monosodium iodoacetate (MIA)-induced OA rat model attenuated mechanical allodynia, cartilage degradation, and aberrant miR-206/SIRT3 expression, while improving weight-bearing symmetry; furthermore, similar therapeutic benefits-including pain relief, functional recovery, and cartilage protection-were confirmed in a chronic, post-traumatic destabilization of the medial meniscus (DMM) model, with efficacy demonstrated against appropriate AAV control groups. These findings identify the circHIPK2-miR-206-SIRT3 axis as a critical regulator of chondrocyte bioenergetics and OA progression, offering novel therapeutic targets for modulating non-coding RNA networks in joint degeneration.

Keywords:  Mitochondrial respiration; Osteoarthritis-induced nociception; SIRT3; Warburg effect; circHIPK2

DOI:  https://doi.org/10.1007/s10787-025-02106-0
Cardiovasc Res. 2026 Jan 20. pii: cvag011. [Epub ahead of print]

Mitoregulin supports mitochondrial membrane integrity and protects against cardiac ischemia-reperfusion injury.

Colleen S Stein, Xiaoming Zhang, Nathan H Witmer, Edward Ross Pennington, Scott Hahn, Adam C Straub, Saame Raza Shaikh, Ryan L Boudreau.

   AIMS: We and others discovered a highly conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress.
METHODS AND RESULTS: We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally relevant role for Mtln in cardioprotection.
CONCLUSION: Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

Keywords:  Cyb5r3; cardiolipin; cardioprotection; cristae; docosahexaenoic acid; ischemia-reperfusion; mitochondria; monolysocardiolipin; permeability transition; triglycerides

DOI:  https://doi.org/10.1093/cvr/cvag011
Front Pharmacol. 2025 ;16 1725973

Bone-targeted mitochondrial delivery via magnetic-temperature responsive artificial cells for repairing age-related fractures.

Shihao Nie, Yue Yu, Rong Yan, Taoran Liu, Yue Du, Zhuojing Luo, Shengyou Li, Jinghui Huang.

   Background: Age-related bone diseases, such as osteoporosis and degenerative joint disorders, pose a significant global health challenge, leading to over 9 million fractures annually, which not only diminishes quality of life but also imposes a substantial socioeconomic burden on healthcare systems. A major clinical obstacle in the aging population is the significantly reduced regenerative capacity of bone, often resulting in delayed fracture healing or nonunion fractures. Mitochondria, as the central regulators of cellular energy metabolism, are essential for determining cell fate and supporting tissue regeneration. However, age-associated mitochondrial dysfunction critically impairs these processes. While transplanting healthy mitochondria is a promising therapeutic strategy, its efficacy is severely limited by poor targeting efficiency and inherent fragility of mitochondria in circulation. Developing an efficient mitochondrial transplantation for elderly fractures is of great importance.
Methods: We constructed artificial cell microspheres (Fmito@ACs) containing mitochondria of fetal mouse mesenchymal stem cells and conducted systematic characterization of them. In vitro experiments evaluated the effects of Fmito@ACs on the functions of primary osteoblasts, and its role in delaying cellular senescence was analyzed through β-galactosidase staining and immunofluorescence analysis of senescence markers (P21 and γH2A.X). Its ability to restore mitochondrial function was assessed by measuring ROS, morphology, and energy metabolism. In animal experiments, labeled Fmito@ACs were tracked using IVIS Spectrum system, and their targeted accumulation at fracture sites guided by an external magnetic field was verified. The biosafety of the system was evaluated via H&E staining and hepatic/renal function parameters. Bone healing was monitored via micro-CT, X-ray, and histology on days 7, 14, and 21, while related gene expression and molecular mechanisms were analyzed by qPCR and transcriptome sequencing.
Results: Fmito@ACs were successfully constructed and characterized, indicating a protective effect on mitochondria. The system ameliorated senescence in aged BMSCs, promoting osteogenesis by enhancing mitochondrial fusion and aerobic glycolysis. In an aged fracture model, Fmito@ACs showed targeted accumulation and biosafety, significantly improving healing.
Conclusion: As an efficient mitochondrial-targeted delivery system, Fmito@ACs fully exploits the anti-aging effects of young mitochondria, providing a new strategy and theoretical basis for the treatment of age-related fractures.

Keywords:  age-related fractures; anti-aging; artificial cells; magnetic-temperature responsive; mitochondria

DOI:  https://doi.org/10.3389/fphar.2025.1725973
Life Sci Space Res (Amst). 2026 Jan;pii: S2214-5524(25)00127-0. [Epub ahead of print]48 156-165

Differential regulation of mitochondrial quality control in skeletal muscle by HZE radiation exposure and partial weightbearing in mice.

Carla Mc Nascimento, James D Fluckey, Florence Lima, Brandon R Macias, Yasaman Shirazi-Fard, Elizabeth S Greene, Leslie A Braby, Susan A Bloomfield, Michael P Wiggs.

  Spaceflight places astronauts under both reduced mechanical loading and ionizing radiation, each of which can compromise skeletal muscle health. We investigated whether 21 days of simulated lunar gravity (one sixth G) with or without a single 0.5 Gy dose of 28Si heavy ion radiation alters transcriptional regulators of mitochondrial quality control in mouse gastrocnemius muscle. Female BALB/cByJ mice were assigned to four groups: Sham + 1 G (SHAM+CC), Rad + 1 G (RAD+CC), Sham + G/6 (SHAM+G/6), Rad + G/6 (RAD+G/6) and relative mRNA levels of key regulators of mitochondrial biogenesis, mitophagy, dynamics and electron transport chain content were measured by quantitative RT-PCR. Radiation significantly suppressed PGC-1α (p = 0.035) and TFAM (p = 0.051) transcripts and reduced LC3b (p = 0.033) and Park2 (p = 0.007) expression; no effects of simulated lunar gravity or interaction effects were detected. Composite scores confirmed suppression of biogenesis (p = 0.029) and a trend toward reduced mitophagy (p = 0.057). Transcripts encoding oxidative phosphorylation subunits and fusion and fission factors remained unchanged, suggesting preserved mitochondrial content and network homeostasis at day 21. These findings indicate that a single space relevant heavy ion exposure selectively disrupts early transcriptional steps of mitochondrial turnover without immediately altering organelle abundance of transcripts for electron transport chain or dynamics; in contrast simulated lunar gravity alone did not elicit changes in these pathways.

Keywords:  Autophagy; Biogenesis; Dynamics; Fission; Fusion; Spaceflight

DOI:  https://doi.org/10.1016/j.lssr.2025.10.008
PeerJ. 2026 ;14 e20494

The dual role of activating transcription factor 4: from cellular stress sentinel to cardiovascular disease intervention.

Yaping Wang, Jie Yuan, Feifan Wang, Hong Ma.

  As the master orchestrator of integrated stress response, activating transcription factor 4 (ATF4) operates as a central molecular switch that directs cellular fate toward survival or death by regulating genes associated with oxidative stress, endoplasmic reticulum stress, apoptosis, ferroptosis and metabolism. The functional outcome of ATF4 activation is critically dependent on the context: it usually contributes to cellular adaption and survival under mild or transient stress, yet triggers cell death when stress is severe or prolonged. Dysregulation of this dichotomous function has been implicated in a variety of diseases, such as cancer, neurodegenerative disease, metabolic disease, etc., highlighting ATF4 as a potential therapeutic target. Recently, growing evidence has further underscored the dual roles of ATF4 as the guardian or executioner in cardiovascular disorders, such as coronary heart disease, cardiomyopathy, arrhythmia, valvular heart disease, heart failure and cardiovascular aging. Here in this review, we systematically decode the context-dependent opposing roles of ATF4 in cardiovascular diseases and also highlight the underlying regulatory mechanisms, thereby providing a rationale for developing context-specific therapeutic strategies targeting ATF4 for the personalized management of cardiovascular disorders.

Keywords:  ATF4; Endoplasmic reticulum stress; Ferroptosis; Integrated stress response; Oxidative stress; Serine biosynthesis

DOI:  https://doi.org/10.7717/peerj.20494
Extracell Vesicles Circ Nucl Acids. 2025 ;6(4): 724-727

Blood, sweat, tears and fibrosis: when overtraining injures the liver.

Enis Kostallari.

  The crosstalk between the skeletal muscles and the liver is receiving growing attention, as patients with chronic liver disease often develop a loss of skeletal muscle mass. In these patients, particularly those with metabolic dysfunction-associated steatotic liver disease, physical exercise improves insulin sensitivity and hepatic steatosis. However, excessive exercise may impair mitochondrial function, inflammation, and liver health. The study by Liu et al. demonstrates that overtraining promotes liver fibrosis through myocyte-derived small extracellular vesicles. Here, we comment on the novelty of these findings and areas to be developed in the future.

Keywords:  Liver fibrosis; condensates; extracellular vesicles; lactate; skeletal muscle liver axis

DOI:  https://doi.org/10.20517/evcna.2025.56
FASEB J. 2026 Jan 31. 40(2): e71485

Integration of Bioinformatics and Experiments to Identify Mitochondrial Metabolism and Immune Infiltration Characterization in Lung Injury and Post-Injury Lung Fibrosis.

Cong-Cong Chen, Shi-Qing Huang, Pei-Hui Chen, Chu-Yue Zhong, Hong-Wei Wang, Zi-Xiao Han, Qing-Qing Hu.

  Acute lung injury (ALI) and subsequent lung fibrosis involve critical roles of mitochondrial metabolism and immune inflammation. This study identified 10 hub mitochondrial-related differentially expressed genes (MitoDEGs) linked to these conditions through integrated bioinformatics screening and protein-protein interaction analysis. Functional enrichment associated these MitoDEGs with energy conversion, oxidative stress, and fatty acid metabolism in ALI and fibrosis. Immune infiltration analysis revealed prominent M1 macrophage infiltration in ALI, with significant correlations between each hub MitoDEG and immune cells. In vivo and in vitro experiments confirmed dynamic expression changes of key MitoDEGs, including Uqcrq and Ndufb6, alongside disturbances in mitochondrial, oxidative stress, and lipid metabolism pathways. Multiplex immunohistochemistry showed increased Ndufb6-positive alveolar epithelial cells during inflammatory infiltration. Functional studies demonstrated that Ndufb6 deficiency attenuated mitochondrial fragmentation, respiratory dysfunction, and oxidative stress under inflammatory and fibrotic stimuli. Preliminary evaluation also suggested the clinical relevance of Ndufb6 and Uqcrq. These findings highlight MitoDEGs at the intersection of mitochondrial metabolism and immune response, offering new mechanistic and therapeutic insights for ALI and post-injury lung fibrosis.

Keywords:  acute lung injury; bioinformatics; immune infiltration; lung fibrosis; mitochondrial metabolism

DOI:  https://doi.org/10.1096/fj.202503653R